The present invention relates generally to benzopyranone aci-reductone compounds and the processes for their manufacuture, and pharmaceutical preparations thereof.
The invention further relates to the use of such compounds to inhibit collagen-induced blood platelet aggregation and secretion of serotonin, which a vasoconstrictor is present in platelets. The invention further relates to the pharmaceutical use of such compounds in the treatment of thromboembolic disorders.
The antiaggregatory activites of clofibric acid 1 and 2-hydroxytetronic acid aci-reductone 2 compounds are of interest since blood platelets are involved in the genesis of atherosclerosis. Compounds, such as clofibric acid 1 and 2-hydroxytetronic acid aci-reductone 2 inhibit collagen-induced human platelet aggregation and secretion of [.sup.14 C]-serotonin in a concentration-dependent manner at equivalent doses, as reported in Witiak et al., J. Med Chem. 25:90 (1982). Compounds 1 and 2 inhibit platelet function by a similar mechanism, involving arachidonic acid release. It also was previously unknown that redox analogues such as compound 2 function as antioxidants in membranes or interfere with free radical processes involved in the biosynthetic elaboration of cyclic prostaglandin endoperoxides (PGG.sub.2 and PGH.sub.2) and subsequently thromboxane A.sub.2 from arachidonic acid. ##STR2##
Clofibric acid 1 inhibits collagen- and adenosine diphosphate (ADP)-induced human platelet activation with little activity against arachidonic acid-induced aggregation. The effect of clofibric acid is attributed to both a blockade of arachidonic acid release from phospholipids and of subsequent arachidonic acid metabolism in human platelet preparations. Also, Vargaftig et al., in J. Biochem. Pharmac. 30:263 (1981) related that clofibrate therapy in hyperlipidemic patients reverses the hyper-aggregatory responses to inducers of the prostaglandin-dependent pathway.
One benzopyranone aci-reductone compound 5 has been synthesized using a lengthy synthetic route, as described in Ghosh, K. C., J. Indian Chem. Soc., 24:323-326 (1947), from the salicylate compound 3. Reaction with acetoxyacetyl chloride afforded an intermediate compound 4 (93%) which upon reaction with Na in refluxing benzene afforded benzopyranone aci-reductone compound 5 (no yield reported). Attempted repetition of the process described in Ghosh to convert the intermediate compound 4 to benzopyranone aci-reductone 5 were unsuccessful. ##STR3##
The benzophyranone aci-reductone 5 compound was prepared, as described in Schank, K., et al., Chem. Ber., 114:1958-1962 (1981), from the 4-hydroxycoumarin compound 6. This four-step conversion involved reaction with TsN.sub.3 in DMF-Et.sub.3 N affording the azo compound 7 which upon treatment with t-BuOCl in HCO.sub.2 H produced the compound 8. The reduction of 8 with NaI, Na.sub.2 S.sub.2 O.sub.5 afforded 9. Subsequent acid catalyzed hydrolysis yielded 5. ##STR4## 7, R,R'.dbd..dbd.N.sub.2 8, R.dbd.Cl, R'.dbd.O.sub.2 CH
9, R.dbd.H, R'.dbd.O.sub.2 CH
To summarize, the literature contains reference only to the preparation of the benzopyranone aci-reductone compound 5 using a lengthy synthetic sequence. Furthermore, although the benzopyranone aci-reductone compound 5 was synthesized, such synthesis yielded an inefficient amount of the compound.
Furthermore, the references are limited to the benzopyranone aci-reductone compound 5. There is no mention of the preparation of substituted analogues or their biological activity.